1. Field of the Invention
The present invention relates generally to the field of diagnostics, therapeutics and immunological reagents. More particularly, the present invention provides binding partners of antibodies specific for dendritic cell (DC) antigens. The present invention further provides diagnostic and/or therapeutic agents based on the binding partners or antibodies specific for the binding partners.
2. Description of the Prior Art
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
Bibliographic details of references provided in this document are listed at the end of the specification.
Dendritic cells (DC) are potent cellular activators of primary immune responses (Hart, Blood 90:3245-3287, 1997). Immature myeloid DC in non-lymphoid organs react to, endocytose and process antigens and migrate via blood and lymph to T cell areas of lymphoid organs. Here, the mature cells present foreign peptide complexed to MHC Class II to T cells and deliver unique signals for T-cell activation (immuno-stimulation). They also stimulate B lymphocytes and NK cells. DC undergo differentiation/activation during this process, lose their antigen-capturing capacity and become mature, immuno-stimulatory DC that trigger naïve T-cells recirculating through the lymphoid organs. The lymphoid DC subset may have a different migration pathway and although capable of stimulating allogeneic and autologous T-lymphocytes they have been suggested to have a regulatory function (Grouard et al, J Exp Med 185:1101-1111, 1997). As part of the differentiation/activation process, DCs up-regulate certain relatively selectively-expressed cell surface antigens such as the CMRF44 (CMRF44Ag) and CD83 antigens. DC in the thymus and DCs that do not have an activated co-stimulating phenotype probably contribute to central and peripheral tolerance.
Allogeneic transplantation involves the transfer of material from a host to a recipient. In this process, many foreign antigens are introduced into a host and an immune response results when these foreign antigens are detected by the host's immune system. Initially, an immune response involves interactions between the antigen and antigen-presenting cells (APC) such as dendritic cells. Interstitial donor DC in heart and kidney contribute to (direct) recipient T lymphocyte sensitization to all antigens but recipient DC, after migrating into the donor tissue, can also stimulate (indirect) alloantigen sensitization of recipient T-lymphocytes. Depletion of heart and kidney and pancreatic islet DC appears to prolong allograft survival. Interestingly, during liver transplantation, donor leucocytes, which may include non-activated dendritic cells, appear to generate allogeneic tolerance. DC are also predicted to contribute to both acute and chronic Graft Versus Host Disease (GVHD), the major life threatening complication of allogeneic bone marrow transplantation (BMT). Blood DC counts change during acute GVHD and recent data have suggested that the DC subset constitution of the allogeneic stem cell preparation might relate to GVHD outcome. Recent evidence from a mouse model suggests that host APC contribute to the acute GVHD. DC may in certain circumstance prevent acute GVHD.
Monoclonal antibodies which act at the level of the responder T lymphocyte have been investigated as therapeutic immunosuppression agents in allogeneic transplantation. The CD3 reagent OKT3 (Orthoclone, Cilag) is used routinely to treat acute renal allograft rejection. Campath 1 (CD52) and its variants have been used in solid organ transplant and BMT. More recent attempts to suppress acute GVHD have involved the antibody ABX-CBL (CD147) (Deeg et al, Blood 98:2052-2058, 2001) and anti-IL-2R mAb Daclizumab (Calm et al, Transplantation 60:939-942, 1995). Attempts to interfere with the interaction of the responder T-lymphocyte and an APC have focused on antibodies directed against the co-stimulator molecules CD40, CD80 and CD86 or their ligands. Animal studies suggest that blockade of co-stimulator molecules on DC and other APC induces T cell anergy and prolongation of solid organ grafts (Koenen and Joosten, Blood 95:3153-3161, 2000, Kirk et al, Nat Med 5:686-693, 1999; Kirk et al, Proc Natl Acad Sci USA 94:8789-8794, 1997). The use of CD80, CD86 and CD28 blocking agents prevents acute GVHD in mice (Blazar et al, Blood 85:2607-2618, 1995) and in vitro blockage of allogeneic responses in allogeneic stem cell preparations has been used in clinical BMT with initial encouraging results (Gribben et al, Blood 87:4887-4893, 1996). The use of a reagent that was more selective at targeting differentiated/activated DC might be advantageous.
In humans, at least two populations of DC, the immature myeloid DC and the plasmacytoid DCs, have been identified based on differential expression of CD11c (O'Doherty et al, J Exp Med 178:1067, 1993; O'Doherty et al, Immunol 82:487, 1994) More recent studies have shown that CD11c− DC have a different phenotype and express higher amounts of CD123, and have a morphology and function distinct from CD11c+ DC (Grouard et al, J Exp Med. 185:1101-1111, 1997). These two subsets are denoted as myeloid lineage CD11c+ DC and plasmacytoid CD123+ DC. It is thought unlikely that there is a direct developmental relationship between them (Robinson et al, Eur J Immunol 29:2769-2778, 1999).
Theoretically, monoclonal antibodies directed at DC administered to the recipient of a solid organ graft would deplete donor DC (i.e. direct) as well as recipient DC (indirect) as they enter the circulation and initiate antigen presentation pathways. Other donor leucocytes may have immunomodulatory capacity. DC depletion therapy might then be ceased after a short period, allowing tolerance to emerge. Depleting recipient DC may be more efficacious than disrupting co-stimulator pathways. Investigation of this concept has been delayed, however, by the absence of suitable DC reagents. CMRF44 antibody (CMRF44Ab) is an antibody specific for DC and is used for the identification and isolation of human blood DC (Hock et al, Immunology 83:573-581, 1994; Fearnley et al, Blood 89:3708-3716, 1997). The latter authors have shown that the epitope for CMRF44 (i.e. CMRF44Ab) is expressed early in the differentiation of DC from circulating precursor cells. However, the nature of the antigen which is recognized by CMRF44Ab and its role in the regulating DC function has yet to be elucidated.
There is a need, therefore, to be able to identify DC epitopes which are recognized by CMRF44Ab and use these for the rational design of diagnostic and/or therapeutic agents useful for diagnosing, preventing and/or treating immunological diseases and conditions.